Machine learning to predict early recurrence after oesophageal cancer surgery.

BACKGROUND: Early cancer recurrence after oesophagectomy is a common problem, with an incidence of 20-30 per cent despite the widespread use of neoadjuvant treatment. Quantification of this risk is difficult and existing models perform poorly. This study aimed to develop a predictive model for early recurrence after surgery for oesophageal adenocarcinoma using a large multinational cohort and machine learning approaches. METHODS: Consecutive patients who underwent oesophagectomy for adenocarcinoma and had neoadjuvant treatment in one Dutch and six UK oesophagogastric units were analysed. Using clinical characteristics and postoperative histopathology, models were generated using elastic net regression (ELR) and the machine learning methods random forest (RF) and extreme gradient boosting (XGB). Finally, a combined (ensemble) model of these was generated. The relative importance of factors to outcome was calculated as a percentage contribution to the model. RESULTS: A total of 812 patients were included. The recurrence rate at less than 1 year was 29·1 per cent. All of the models demonstrated good discrimination. Internally validated areas under the receiver operating characteristic (ROC) curve (AUCs) were similar, with the ensemble model performing best (AUC 0·791 for ELR, 0·801 for RF, 0·804 for XGB, 0·805 for ensemble). Performance was similar when internal-external validation was used (validation across sites, AUC 0·804 for ensemble). In the final model, the most important variables were number of positive lymph nodes (25·7 per cent) and lymphovascular invasion (16·9 per cent). CONCLUSION: The model derived using machine learning approaches and an international data set provided excellent performance in quantifying the risk of early recurrence after surgery, and will be useful in prognostication for clinicians and patients.

ANTECEDENTES: la recidiva precoz del cáncer tras esofaguectomía es un problema frecuente con una incidencia del 20-30% a pesar del uso generalizado del tratamiento neoadyuvante. La cuantificación de este riesgo es difícil y los modelos actuales funcionan mal. Este estudio se propuso desarrollar un modelo predictivo para la recidiva precoz después de la cirugía para el adenocarcinoma de esófago utilizando una gran cohorte multinacional y enfoques con aprendizaje automático. MÉTODOS: Se analizaron pacientes consecutivos sometidos a esofaguectomía por adenocarcinoma y que recibieron tratamiento neoadyuvante en 6 unidades de cirugía esofagogástrica del Reino Unido y 1 de los Países Bajos. Con la utilización de características clínicas y la histopatología postoperatoria se generaron modelos mediante regresión de red elástica (elastic net regression, ELR) y métodos de aprendizaje automático Random Forest (RF) y XG boost (XGB). Finalmente, se generó un modelo combinado (Ensemble) de dichos métodos. La importancia relativa de los factores respecto al resultado se calculó como porcentaje de contribución al modelo. RESULTADOS: En total se incluyeron 812 pacientes. La tasa de recidiva a menos de 1 año fue del 29,1%. Todos los modelos demostraron una buena discriminación. Las áreas bajo la curva ROC (AUC) validadas internamente fueron similares, con el modelo Ensemble funcionando mejor (ELR = 0,791, RF = 0,801, XGB = 0,804, Ensemble = 0,805). El rendimiento fue similar cuando se utilizaba validación interna-externa (validación entre centros, Ensemble AUC = 0,804). En el modelo final, las variables más importantes fueron el número de ganglios linfáticos positivos (25,7%) y la invasión linfovascular (16,9%). CONCLUSIÓN: El modelo derivado con la utilización de aproximaciones con aprendizaje automático y un conjunto de datos internacional proporcionó un rendimiento excelente para cuantificar el riesgo de recidiva precoz tras la cirugía y será útil para clínicos y pacientes a la hora de establecer un pronóstico.

Proximal Resection Margin in Ivor-Lewis Oesophagectomy for Cancer.

OBJECTIVE: The purpose of this study was to investigate whether a long proximal oesophageal resection margin (PRM) is associated with improved survival after oesophagectomy for cancer and to identify the optimal margin to aim for in this patient group. METHODS: A prospectively maintained database identified 174 patients who underwent Ivor-Lewis oesophagectomy for cancer. Demographic, clinical, and pathological data were collected. X-tile software was used to identify the optimal resection point. Two models were analysed: single point resection with comparison of two groups (short and long), and two resection points with three groups (short, medium, and long) to provide a range. RESULTS: The median PRM was 4.0 cm (interquartile range: 2.5-6.0 cm). After adjustment for significant confounders, multivariable Cox PH analysis demonstrated that the optimal resection margin was 1.7 cm, and in the three-group analysis the optimum PRM was between 1.7 and 3 cm. In the two-group analysis, the long margin had no effect on DFS (p = 0.37), but carried a significantly improved overall survival (hazard ratio [HR] = 0.46, 95 % confidence interval [CI] 0.25-0.87, p = 0.02). In the three-group analysis, the medium and long groups had improved OS compared with the short group (on average 54 %, HR ≥ 0.45, p ≤ 0.04). The 5-year disease-free and overall survival rates were highest in the medium PRM group (48 and 57 % respectively). CONCLUSIONS: Optimal survival following oesophagectomy for cancer is achieved with a PRM > 1.7 cm, but a PRM > 3 cm does not yield a further survival advantage. Thus, the optimal PRM is likely to be between 1.7 and 3 cm.

Isavuconazonium sulfate for the treatment of fungal infection.

Isavuconazole is a new azole antifungal drug with a broad antifungal spectrum that includes yeasts, molds and dimorphic fungi. Its prodrug, isavuconazonium sulfate, is currently approved in the United States and Europe for the treatment of the two of the most common and most challenging invasive fungal infections in clinical practice, invasive aspergillosis and invasive mucormycosis. It is available in both oral and intravenous formulations for once-a-day dosing and has favorable safety profile and drug interaction potential in comparison to voriconazole. Its role in the treatment of other fungal infections, besides aspergillosis and mucormycosis, remains to be determined. Similarly, its efficacy in prophylaxis against invasive fungal infections or its utility in patients with prior azole exposure is yet to be elucidated in clinical studies.

Minimal residual disease testing after stem cell transplantation for multiple myeloma.

Increased use of novel agents and autologous stem cell transplantation has led to a significant improvement in PFS and overall survival in patients with multiple myeloma. Despite improved treatment strategies, most patients eventually relapse due to persistent low levels of disease in the bone marrow. Increasingly sensitive methods to measure or detect such disease have been evaluated, including multi-parametric flow cytometry, PCR, next-generation sequencing and imaging modalities. The following literature review examines current methods for detecting and monitoring minimal or measurable residual disease (MRD) in the post-transplant setting. Improved methods for detecting MRD will refine the current definitions of remission and could guide treatment approaches.

Endemic fungal infections in solid organ and hematopoietic cell transplant recipients enrolled in the Transplant-Associated Infection Surveillance Network (TRANSNET).

BACKGROUND: Invasive fungal infections are a major cause of morbidity and mortality among solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients, but few data have been reported on the epidemiology of endemic fungal infections in these populations. METHODS: Fifteen institutions belonging to the Transplant-Associated Infection Surveillance Network prospectively enrolled SOT and HCT recipients with histoplasmosis, blastomycosis, or coccidioidomycosis occurring between March 2001 and March 2006. RESULTS: A total of 70 patients (64 SOT recipients and 6 HCT recipients) had infection with an endemic mycosis, including 52 with histoplasmosis, 9 with blastomycosis, and 9 with coccidioidomycosis. The 12-month cumulative incidence rate among SOT recipients for histoplasmosis was 0.102%. Occurrence of infection was bimodal; 28 (40%) infections occurred in the first 6 months post transplantation, and 24 (34%) occurred between 2 and 11 years post transplantation. Three patients were documented to have acquired infection from the donor organ. Seven SOT recipients with histoplasmosis and 3 with coccidioidomycosis died (16%); no HCT recipient died. CONCLUSIONS: This 5-year multicenter prospective surveillance study found that endemic mycoses occur uncommonly in SOT and HCT recipients, and that the period at risk extends for years after transplantation.

Outcomes of transplantation using organs from a donor infected with Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae.

Transmission of pathogens from donor to recipient is a potential complication of organ transplantation. Herein, we describe the clinical course and outcomes of 4 transplant recipients who received tissues from a donor with multi-organ infection with Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae. Recipient 1 underwent simultaneous liver and kidney transplantation for alpha-1 antitrypsin deficiency and alcohol-related cirrhosis, and acute tubular necrosis, respectively. Soon after transplantation, he developed an infected hematoma and peritonitis due to KPC-producing K. pneumoniae despite receiving tigecycline prophylaxis. He was treated with a prolonged course of tigecycline, amikacin, and meropenem, in conjunction with surgical evacuation and percutaneous drainage of the infected fluid collections. Recipient 2 underwent living-donor liver transplantation for cholangiocarcinoma and primary sclerosing cholangitis using vein graft from the donor infected with KPC-producing K. pneumoniae. Culture of the preservation fluid containing the vein graft was positive for KPC-producing K. pneumoniae. The patient received preemptive amikacin and tigecycline, and he did not develop any infection (as evidenced by negative surveillance blood cultures). The isolates from the donor and Recipients 1 and 2 were indistinguishable by pulsed-field gel electrophoresis. Recipients 3 and 4 underwent kidney and heart transplantation, respectively; both patients received perioperative tigecycline prophylaxis and did not develop infections due to KPC-producing K. pneumoniae. All transplant recipients had good short-term outcomes. These cases highlight the importance of inter-institutional communication and collaboration to ensure the successful management of recipients of organs from donors infected with multidrug-resistant organisms.

False-positive Aspergillus galactomannan assay in solid organ transplant recipients with histoplasmosis.

Post-transplantation histoplasmosis may be acquired via inhalation, may result from endogenous reactivation, or may be derived from the allograft. The Histoplasma and Aspergillus enzyme-linked immunoassays are increasingly being relied upon for rapid diagnosis of fungal infections, especially in immunocompromised patients. We describe 4 cases of solid organ transplant recipients who had histoplasmosis and a falsely positive Aspergillus galactomannan (GM) obtained from the serum or bronchoalveolar lavage (BAL) fluid. We also report our experience, testing for Histoplasma antigen (Ag) in specimens positive for Aspergillus GM. From January 2007 through December 2010, of 2432 unique patients who had positive Aspergillus GM tests, 514 (21%) were tested for Histoplasma Ag, and 27 were found to be positive. Most specimens that tested positive for both Aspergillus and Histoplasma were obtained by BAL. False-positive tests for Aspergillus GM can occur in immunosuppressed patients who have histoplasmosis, and may obscure the correct diagnosis.

Efficacy and safety of rifampin containing regimen for staphylococcal prosthetic joint infections treated with debridement and retention.

The aim of this study was to evaluate the efficacy and safety of rifampin for Staphylococcus aureus (SA) or coagulase negative staphylococci (CNS) prosthetic joint infection (PJI) treated with debridement and retention (D/R). We calculated the treatment failure cumulative incidence (TF) of a cohort of 101 patients with SA or CNS PJI treated with D/R and antimicrobial therapy. The effect of the use of a rifampin-based regimen was evaluated. Cox proportional hazards regression evaluated the association between treatment and time-to-TF controlling for the propensity to treat with rifampin and temporal confounders. Seven percent (1/14) of the prospective rifampin-treated patients, 32% (10/31) of the historical rifampin-treated patients and 38% (21/56) of the historical non-rifampin treated patients developed TF. After controlling for the propensity to treat with rifampin and American Society of Anesthesia scores, patients in the prospective cohort had a lower risk of TF compared to patients in the historical cohort not treated with rifampin (HR 0.11; 95%CI 0.01-0.84). None (0/14) of the patients in the prospective study developed hepatotoxicity. The outcome of staphylococcal PJI treated with D/R and rifampin-based regimens was better when compared with a historical cohort treated without rifampin.

Risk factor analysis of Histoplasma capsulatum fungemia.

The primary objective of the study was to investigate the risk factors for Histoplasma capsulatum fungemia. We conducted a retrospective case-control study among patients with histoplasmosis seen at Mayo Clinic in Rochester from 1 January 1991 through 31 December 2005. Blood cultures were prepared from specimens obtained from 111 patients with a diagnosis of histoplasmosis of which 55 had demonstrated H. capsulatum fungemia whereas the cultures of the remaining 56 patients were negative. The mean age of the patients was 56 years, of which 70% men and 95% were white. In univariate analysis, immunocompromised status (OR 2.9, P=0.008), peripheral leukocyte count (WBC)<3000 cells/mm(3) (OR 7.3, P<0.001), albumin<3.5 g/ dl (OR 3.1, P=0.018), and Charlson score of>4 (OR 2.9, P=0.022) were associated with H. capsulatum fungemia, but age>55 years was not (OR 1.4, P=0.38). In multivariable analysis, immunocompromised status (OR 2.4, P=0.043) and WBC<3000 cells/mm(3) (OR 6.5, P=0.001) remained significant factors associated with H. capsulatum fungemia. Immunocompromised status and WBC<3000 cells/ mm(3) are independent risk factors for the development of H. capsulatum fungemia.

Chorioretinitis and vitreitis due to Tropheryma whipplei after transplantation: case report and review.

Whipple's disease is a very rare chronic multisystemic bacterial disease characterized by diarrhea, malabsorption, fever, and polyarthritis. Ocular manifestations occur very rarely. Previous reports have suggested that the use of immunosuppressive drugs appears to accelerate or exacerbate the clinical course of Whipple's disease; however, the illness has yet to be reported in the setting of transplantation. Herein, we describe what we believe is the first reported case of Whipple's disease after transplantation. The patient is a 51-year-old woman who developed progressive visual floaters and blurring of vision 30 years after living-related kidney transplantation for an autosomal-dominant polycystic kidney disease. Her allograft was functioning well on maintenance immunosuppressive therapy with azathioprine and prednisone when she developed visual abnormalities. Transient weight loss, gastrointestinal symptoms, and migratory polyarthralgia predated the onset of ocular disease by several years. The diagnosis of Whipple's bilateral vitreitis and chorioretinitis was confirmed by polymerase chain reaction analysis demonstrating Tropheryma whipplei nucleic acid in vitreous fluid and peripheral blood sample as well as by demonstration of the bacilli by cytopathology. Intraocular vancomycin, intravenous ceftriaxone, and prolonged course of oral trimethoprim-sulfamethoxazole therapy led to clinical improvement and recovery of visual acuity.

Lyme disease followed by human granulocytic anaplasmosis in a kidney transplant recipient.

We report the case of a kidney transplant recipient who developed Lyme disease, followed by human granulocytic anaplasmosis (HGA) 3 years later. A review of all previously published cases of Lyme disease (3 cases), HGA (5 cases), and human monocytic ehrlichiosis (HME) (5 cases) in transplant recipients is presented. Manifestations of the cases reviewed were similar to those of non-transplant patients. There appeared to be no obvious correlation between immunosuppression and the occurrence of the illness in the transplant recipients. Serologic testing failed to make a diagnosis in 1 patient with HME in the literature and in our patient with HGA, but molecular tests established the diagnosis in both cases. Tandem infection was observed in 1 patient with two episodes of HME 2 years apart. A high index of suspicion for tick-borne illnesses and appropriate prevention measures are needed for transplant patients with epidemiologic risk factors.

Identifying risk factors for two complication types for neonatal intensive care patients (NICU).

This paper discusses the results of applying artificial neural networks to predicting complication for neonatal intensive care patients. Risk factors that lead to necrotizing entero-colitis or broncho-pulmonary dysplasia were identified. Future work will expand this work to other outcomes and add probability information to the estimations.

Predicting clinical outcomes for newborns using two artificial intelligence approaches.

Two different approaches, based on artificial neural networks (ANN) and fuzzy logic, were used to predict a number of outcomes of newborns: How they would be delivered, their 5 minute Apgar score, and neonatal mortality. The goal was to assess whether the methods would be comparable or whether they would perform differently for different outcomes. The results were comparable for Correct Classification Rate (CCR) and Specificity (true negative cases). Sensitivity (true positive cases) was slightly higher for the back-propagation feed-forward ANN than using the Fuzzy-Logic Classifier (FLC). Since this is one single database and a very large one, it is possible that the FLC would perform better than the ANN for very small databases, as shown by some of the co-authors in the past. The next step will be to test a small database with both methods to assess strengths and weaknesses with the intent to use both if needed with some medical data in the future.

The fluoroquinolones.

The quinolones are broad-spectrum antibacterial agents that have a novel mechanism of action. As synthetic compounds, these agents have been developed extensively to optimize antimicrobial activity, pharmacokinetic properties, and drug safety. Although earlier quinolones were effective only in the genitourinary and gastrointestinal tracts and only had activity against aerobic gram-negative bacteria, newer quinolones have wider potential applications and a broader spectrum of activity. Some of the newer quinolones will have a role in the treatment of community-acquired pneumonia and intra-abdominal infections. Ciprofloxacin remains the most potent quinolone against Pseudomonas aeruginosa. Among the quinolones, important differences exist in renal and hepatic elimination and dose-adjustment regimens. Although there are many Food and Drug Administration-approved indications for some of the newer quinolones, the quinolones are the drug of choice for only a few infections. Quinolone-resistant bacteria are being increasingly identified and emerge under selective pressure created by extensive use.

Disseminated Kaposi's sarcoma after heart transplantation: association with Kaposi's sarcoma-associated herpesvirus.

BACKGROUND: Kaposi's sarcoma is an endothelial tumor rarely diagnosed after heart transplantation. We report on a patient originally from Africa in whom Kaposi's sarcoma developed in association with Kaposi's sarcoma-associated herpesvirus. METHODS: A man from Ghana had constitutional symptoms associated with multiple pulmonary nodules that developed 3 months after heart transplantation. Kaposi's sarcoma was diagnosed by thorascopic biopsy. Treatment consisted of reducing immunosuppression therapy and adding famciclovir treatment. Symptoms resolved within 1 month after treatment, and no disease progression was observed for 5 months. The patient died suddenly 8 months after heart transplantation; autopsy revealed occlusion of the left anterior descending coronary artery and grade 3A rejection. Extensive Kaposi's sarcoma was observed in the lungs and gastrointestinal tract at autopsy. RESULTS: Pathologic analysis of the tumor demonstrated features consistent with Kaposi's sarcoma. Polymerase chain reaction and in situ hybridization demonstrated the presence of Kaposi's sarcoma-associated herpesvirus. CONCLUSION: Kaposi's sarcoma rarely is diagnosed after transplantation. Patients infected with Kaposi's sarcoma-associated herpesvirus may be at increased risk. Screening for Kaposi's sarcoma-associated herpesvirus may be indicated in patients at risk. The role of antiviral medications and immunization in the treatment and prevention of the disorder is unknown.

Respiratory syncytial virus pneumonitis-induced diffuse alveolar damage in an autologous bone marrow transplant recipient.

A 24-year-old woman with recurrent Hodgkin's lymphoma, stage IIB nodular sclerosing type, underwent an autologous bone marrow transplantation. Forty-five days after transplantation, an upper respiratory tract infection developed that progressed to respiratory distress necessitating mechanical ventilation. An open-lung biopsy demonstrated diffuse alveolar damage. After an extensive search for the cause of the respiratory compromise, we detected respiratory syncytial virus in a bronchoalveolar lavage specimen. The patient was immediately treated with aerosolized ribavirin and intravenous immunoglobulin; her symptoms resolved, and she was extubated 4 days after initiation of therapy.

Prophylaxis of cytomegalovirus infection in liver transplantation: a randomized trial comparing a combination of ganciclovir and acyclovir to acyclovir. NIDDK Liver Transplantation Database.

BACKGROUND: The optimal prophylactic regimen to prevent cytomegalovirus (CMV) infection and disease in orthotopic liver-transplant patients remains to be established. We tested whether a combination of intravenous ganciclovir (GCV) followed by high dosages of oral acyclovir (ACV) for 4 months provided a higher degree of protection from CMV than oral ACV alone. METHODS: One hundred sixty-seven liver-transplant recipients were randomized to receive 120 days of antiviral treatment starting at the time of transplantation consisting of either ACV 800 mg orally four times daily (n=84) or 14 days of GCV 5 mg/kg intravenously every 12 hr followed by oral ACV 800 mg four times daily (n=83). Prospective laboratory and clinical surveillance was performed to determine primary endpoints (onset of CMV infection and CMV disease) and secondary endpoints (rates of fungal and bacterial infection, allograft rejection, and survival after transplantation). One-year event rates are presented as cumulative percentages. RESULTS: During the first year after transplantation, CMV infection developed in 57% of patients treated with ACV and in 37% of patients treated with GCV + ACV (P=0.001). CMV disease developed in 23% of patients treated with ACV and in 11% of patients treated with GCV + ACV (P=0.03). In seronegative recipients of allografts from CMV-seropositive donors (D+/R-), CMV disease developed in 58% of patients treated with ACV and in 25% of patients treated with GCV + ACV (P=0.04). In the D+/R- group, 54% of patients treated with ACV and 17% of patients treated with GCV + ACV developed infection with Candida albicans (P=0.05). CONCLUSIONS: Prophylaxis of CMV infection in liver-transplant patients with 14 days of intravenous GCV followed by high-dosage oral ACV is more effective than high-dosage oral ACV alone at reducing CMV infection and disease, even for patients in the D+/R- CMV serological group.

Development of monoclonal gammopathy precedes the development of Epstein-Barr virus-induced posttransplant lymphoproliferative disorder.

Epstein-Barr virus (EBV)-induced posttransplant lymphoproliferative disorder (PTLD) develops in 3% to 10% of solid organ transplant recipients with a resultant mortality of up to 70%. Unfortunately, there is no current marker which identifies patients who will develop this disease. We therefore conducted a risk factor analysis of variables that might predict the development of PTLD. Specifically, since EBV may cause both PTLD and the development of monoclonal proteins (M protein), we sought to determine if the development of an M protein preceded and therefore might serve as a predictive marker of subsequent PTLD. Before and after liver transplantation, 201 patients were evaluated for the presence of urine and serum M proteins. Patients were followed to monitor the development of PTLD for a mean of 1,733 days. PTLD developed in seven patients (3.5%), three (43%) of whom died from disseminated PTLD. PTLD was classified as polymorphous in six patients and monomorphous in one patient. Fifty-seven patients (28%) developed an M protein after transplantation: five of seven patients (71%) with PTLD and 52/194 (27%) of patients without PTLD. Multivariate risk factor analysis for the development of an M protein after transplantation identified cytomegalovirus (CMV) donor seropositivity (P = 0.0002) and postoperative symptomatic CMV infection (P = 0.019) as risk factors. Whereas EBV serostatus of either the donor or recipient was not found to be a risk factor for the occurrence of either an M protein or PTLD, the development of a serum immunoglobulin M (IgM) M protein (P = 0.04) and of any urine M protein (P = 0.01) was identified by univariate analysis as being associated with the development of PTLD. Further studies are needed to determine the predictive value of M proteins as a marker for PTLD. Until such time, the development of serum or urine M protein should heighten the suspicion of developing PTLD.